We wish to study the drug Kineret in patients suffering from moderate-to-severe traumatic brain injury MedDRA version: 20.1 Level: LLT Classification code 10060690 Term: Traumatic brain injury System Organ Class: 100000004863 MedDRA version: 20.1 Level: PT Classification code 10051288 Term: Central nervous system inflammation System Organ Class: 10029205 - Nervous system disorders
Conditions
Interventions
Trade Name: Kineret
Product Name: Kineret
Pharmaceutical Form: Injection
INN or Proposed INN: Anakinra
CAS Number: 143090-92-0
Other descriptive name: Recombinant human Interleukin-1 receptor antagoni
Sponsors
Cambridge University Hospitals NHS Foundation Trust and the University of Cambridge
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: • Have given written informed consent to participate provided by the patient's legal representative or by agreement with an independent health provider (as the patient will initially lack capacity). • Aged 18-64 years. • Head injury patients (Glasgow Coma Scale 3-13), requiring ventilation, sedation and a cranial access device for their clinical management for at least 72 hours. • Head injury should be compatible with survival. • Possible to deliver the first dose of IMP within 12 hours after trauma. Are the trial subjects under 18? no Number of subjects for this age range: 0 F.1.2 Adults (18-64 years) yes F.1.2.1 Number of subjects for this age range 60 F.1.3 Elderly (>=65 years) no F.1.3.1 Number of subjects for this age range 0
Exclusion criteria
Exclusion criteria: • Head injury unlikely to survive 5 days (CT evidence of above as judged by clinical team, bilateral fixed and dilated pupils). • Not able to provide the initial dose of IMP within 12 hour after trauma. • Follow up not possible • Not suitable for insertion of Cranial Access Device (bleeding diathesis) • Participation in other CTIMP - As per the SmPC • Immunosuppression (evidence of neutropenia (ANC <1.5 x 109/l), immunosuppression secondary to immunomodulatory medications, chemotherapy or radiation therapy in the 3 months preceding study entry) • Severe Renal Insufficiency or End Stage Renal Disease (defined as a creatinine clearance <30 ml/min) • Pregnancy/Nursing mothers • Known hypersensitivity to E. coli derived products • Administration of live vaccine • Known presence or suspicion of active bacterial, fungal or viral infections, including tuberculosis, or HIV infection or hepatitis B or C infection. • Uncontrolled clinically significant hematologic, pulmonary, endocrine, metabolic, gastrointestinal, or hepatic disease as judged by the investigator. • Concurrent treatment with TNF-alpha antagonists (Etanercept®).
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: Our primary research aim is to detect a dose-response decrease of pro-inflammatory cytokines (components of the immune system called tumor necrosis factor alpha and interferon gamma) in the brain parenchyma during the first 48 hours after first dose of the IMP following traumatic brain injury. The cytokine-extraction will be done using the microdialysis which will extract these cytokines from the extracellular fluid of the brain. Our main hypothesis is that following administration of Kineret, there will be a dose-response modification of the inflammatory response, possible to measure using microdialysis probes in brain parenchyma. With escalating dose, and versus placebo, the pro-inflammatory cytokines tumor necrosis factor alpha and interferon gamma, will decrease in the brain parenchyma. The null hypothesis is that there is no difference in cytokine concentration between an escalating dose of Kineret and placebo. Placebo group (A) will be compared with the intermediate dose of the;Secondary Objective: To determine a dose-response effect of Kineret following traumatic brain injury on: - Patient outcome after 6 and 12 months. - Brain immune system activation ("Microglial" activation) and assessment of special kind of brain injury ("diffuse axonal injury"). - Release of brain enriched proteins to the blood and spinal fluid. - Pressure and amount of oxygen in the injured brain. - Drug delivery to the brain. - Drug safety for the patient (amount of side-effects).;Primary end point(s): The primary endpoint is a dose-dependent difference in cerebral cytokine concentrations following 48 hours of IMP administration, primarily for tumor necrosis factor alpha and interferon gamma.;Timepoint(s) of evaluation of this end point: The cytokine concentration will be sampled and analyzed the first 48-72 hours following injury. | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): To determine a dose-response effect of recombinant human Interlekukin-1 receptor antagonist (Kineret) following traumatic brain injury on several outcome metrics, including: - Clinical outcome by assessing neurological function and recovery using standardized scales (e.g. extended Glasgow Outcome Score, and neuropsychiatric assessment) at 6 months and 1 year. This will provide an estimate of the variability in outcome metrics which will allow a definitive power calculation to be estimated for a phase III study. - Imaging outcome by magnetic resonance imaging, including a technique called diffusion tensor imaging (DTI) at repeated time points to determine degree of brain injury on the connectivity between the brain’s axons (connections) globally as well as in the locality of the microdialysis catheter (a semipermeable membrane inserted into affected brain tissue) to monitor brain metabolism and inflammation. - Biochemical outcome by concentrations of protein biomarkers of tissue fate, including S100B, Neurofilament Light (NF-L), microtubule associated protein tau (tau) and amyloid-beta which all have been shown to increase in patients with different brain diseases including traumatic brain injury, Alzheimer’s and multiple sclerosis. - Monitoring outcome by assessing intracranial pressure, cerebral metabolism, brain tissue oxygen as well as alterations in cerebral blood flow. - Pharmacokinetic outcome by measuring how much drug that reaches the affected brain using the microdialysis technique. - Inflammatory outcome by analysing microglial activation, the inflammatory cells of the brain, using positron emission tomography, a radiological technique, during hospital stay. We also wish to see how the body’s immune system reacts by measuring the adaptive immune system’s reactivity toward brain specific proteins as a surrogate marker of injury severity;Timepoint(s) of evaluation of this end point: - Clinical outcome will be assessed at 6 months and | — |
Countries
United Kingdom
Contacts
Public ContactCarrie Bayliss
Cambridge University Hospitals NHS Foundation Trust
Outcome results
None listed